Current Views on Malaria Prophylaxis

A Review Article

Dr Arlene Goldman MB.BCh. MRCP(UK) MACP

The development of resistance to familiar anti-malarials has created confusion
both for Doctors and travellers as to what is the best and most effective anti-malarial to
take and which areas of the World require special precautions. Further difficulties are
created by the serious side-effects encountered on using the newer drugs. This review will
endeavour to elucidate current areas of resistance and recommendations for prophylaxis and
treatment. Great stress is given to the warning that no prophylaxis is foolproof and
failures arise most commonly from not taking the drugs as prescribed. In particular they
must be started 1 week before departure and continued for 4-6 weeks after leaving the
malaria area. Any fever up to 12-18months after leaving a malaria area should arouse
suspicion of malaria and be investigated accordingly. Appropriate advice must be sought
prior to departure from a reputable travel advice centre.

An update from the University of Oxford in Drug Safety 8(4) 1993
stated that a careful risk-benefit analysis is required to balance the risk of acquiring
potentially serious malaria against the risk of harm from the prophylactic agent.
Chloroquine and Proguanil) have an excellent safety record in the recommended dosages.
Recent publicity has been given to side effects of Mefloquine which is used extensively in
areas of resistance to Chloroquine and Proguanil.(Luzzi.GA Peto TE),
Chloroquine-150mgs(base)-2 tablets/week.

Most common side effect - dyspepsia. Pruritis and
exacerbations of psoriasis may occur.In standard doses Retinopathy does not appear to be a
complication when used short term.1

Proguanil-hydrochloride(paludrine)-200mgs/day alone or with weekly

Chloroquine.Used with Chloroquine in pregnant women,children and
others who cannot take mefloquine or doxycycline.1

Mefloquine 250mgs(salt) once per week.Not recommended for patients
taking betablocker drugs or quinidine,for pilots and others who need fine motor
skills,known neurologic or psychiatric disorders,pregnant women in first trimester,or
children less than 15kgs.1 Mefloquine may provoke severe neuropsychiatric reactions with a
frequency of 1 in 15000-20,000 users at the prophylactic dosage.

Pyrimethamine-sulfadoxine (Fansidar) 25mgs of Pyrimethamine and
500mgs of Sulfadoxine/tablet. has been associated with a relatively high incidence of
potentially fatal reactions and is no longer recommended for prophylaxis..May be used for
standby treatment. Should not be taken by pregnant women or if sensitive to
sulphonamides.Serious adverse reactions include Stevens Johnson syndrome,toxic epidermal
necrolysis,agranulocytosis,hypersensitivity pneumonitis and hepatitis.

Pyrimethamine-Dapsone (Maloprim) 1 tablet/week 12.5mgs of
Pyrimethamine and 100mgs of Dapsone. Used with Chloroquine. Not on sale in the USA.
Pyrimethamine-dapsone has been associated with agranulocytosis and should be reserved as a
second line drug for travellers to high risk areas.

Doxycycline Used if unable to take Chloroquine or Mefloquine in high
risk areas and areas of mefloquine resistance in South East Asia.Unsuitable for children
and during pregnancy and lactation. Must be taken after meals standing up and with a lot
of fluid. Use for more than 3 months to be avoided.2

Halofantrine 250mgs/tablet. 2 tablets in one dose,then 2 tabs after
6 hours and 2 more 6 hours after that one.Course repeated 7 days later.Halofantrine-is
well tolerated and has a rapid antimalarial activity.It is more expensive than other
antimalarials and the existence of cross resistance links its usefulness to the demise of
mefloquine.The discovery of a potentially lethal cardiotoxicity associated with
Halofantrine limits its use. Halofantrine lengthens the QT interval especially in those
taking Mefloquine.Sudden deaths have occurred. Was used as standby treatment not
prophylaxis. No longer recommended for standby treatment.2

Quinine Standby treatment not prophylaxis. 300mgs/tablet. 2tabs 3
times per day for 7 days. Note that it is not a suitable standby if mefloquine is used as
a prophylactic.2

Artemisinin or Qinghaosu - Artemesia annua (sweet
wormwood) is found in many parts of the world. In the early 1970's Chinese scientists
recognised its potential for treating malaria and isolated the active
principle,artemesinin or qinghaosu.3

Qinghaosu can be produced from natural sources and has been well
studied.(artemisinin,arteannuin A).A novel ring system present in Yinghaosu was
synthesised and a series of analogues were tested in mice against Plasmodium berghei.The
optimised analogues possessed activity comparable to Qinghaosu.One of the best compounds
Ro(arteflene)was selected for detailed preclinical evaluation. It had low acute toxicity
after oral or subcut administration.4

To combat increasing problems with drug resistance to Plasmodium
falciparum Viet Nam has turned increasingly to the artemisinin derivatives. Oral and
suppository formulations are produced from locally grown plants. These compounds have been
rapidly effective in a large number of studies.5

Arteflene- A synthetic derivative of Yinghaosu was
evaluated extensively against various drug-sensitive and drug-resistant Plasmodium
falciparum in vitro and Plasmodium berghei in mice.The potential therapeutic and
prophylactic activities were studied comparatively with chloroquine, mefloquine, quinine
as well as Qinghaosu and the derivatives artemether and artesunic acid. Experimentally
arteflene proved to be a highly effective antimalarial drug.The suppressive and
prophylactic properties were comparable to chloroquine and superior to Qinghaosu
artemether and artesunic acid.It was consistently rather more active against
drug-resistant than against drug sensitive strains of Plasmodium falciparum. Drug
interactions in vitro and in vivo with Chloroquine,Mefloquine and Quinine revealed an
additive to synergistic effect with arteflene.6

Artemether- The use of drug combinations may be
necessary in areas where drug resistant parasites exist. In eastern Thailand a study was
done using artemether 300mgs single dose followed by mefloquine 750mgs at 24hrs and 500mgs
at 30hrs,or oral artemether 300mgs on day 1,followed by Mefloquine 750mgs at 24hrs and
placebo at 30hrs.No serious adverse effect was seen in either group;mild and transient
nausea and vomiting and loss of appetite were noted.The results suggested that a single
oral dose of artemether(300mgs)can markedly improve the cure rate of mefloquine in
multiple drug resistant malaria.7

Artesunate - Artesunate has been shown to be
effective against Plasmodium falciparum but is associated with a high recrudescence rate.A
study done in Bangkok Hospital for Tropical Diseases compared quinine plus tetracycline
with oral artesunate in patients with acute uncomplicated Plasmodium falciparum
malaria.Oral artesunate had faster parasite and fever clearance times than the combination
but the cure rate was not significantly different.Nausea and dizziness were common with
artesunate. They drew the conclusion that oral artesunate can be considered as an
alternative drug for multiple drug resistant Plasmodium falciparum malaria but adverse
effects especially neurotoxicity must be closely monitored before its widespread use can
be recommended. 8

Pyronaridine a hydroxyanilino-benzonaphthyridine
derivative synthesised in 1970 has been in use in China for more than 10 years(date of
article 1992). The drug is highly effective against Plasmodium falciparum and Plasmodium
vivax.It is efficacious against Chloroquine resistant Plasmodium falciparum in vitro and
in vivo. It has been given orally,IM or by I-V drip and has low toxicity.9

Pyronaridine was synthesised from either 2-aminopyridine or
pyridine.A series of studies revealed it was a promising drug against the erythrocytic
stage of malaria parasites.It showed low toxicity and had no cross-resistance to
chloroquine. A combination of Pyronaridine/Sulfadoxine/Pyrimethamine was used in the
treatment of Chloroquine resistant Plasmodium falciparum in Hainan Province in order to
retard the development of resistance to pyronaridine.A further in vivo test in the Diaoluo
area using the combined formula was used for 5 years(1986-1990).

Drug resistance wad not demonstrated in this study.10 6
Azithromycin-A study was done to determine whether azithromycin 250mgs/day could be an
effective prophylactic agent for Plasmodium falciparum malaria. The study was a controlled
phase 2 trial with two cohorts entered sequentially.The data suggested that azithromycin
has potential to be a well tolerated and effective clinical prophylactic agent for
malaria.Compared with Mefloquine and Doxycycline it has less teratogenicity(class B) in
lab animals but well controlled clinical studies have not been done. A liquid formulation
for young children is being developed.11

Thailand

The Thai-Cambodian border harbours the world's most severe multi-
drug resistant Plasmodium falciparum.12 Plasmodium falciparum in Thailand is highly
resistant to chloroquine and sulfdoxine/pyrimethamine(Fansidar) and there is increasing
resistance to the alternative anti-malarials, quinine and mefloquine.7 The situation is
most serious in the Thai/Cambodia and Thai/Myanmar border areas where multi-resistance
necessitated the shift to the last line drugs-artemisinin derivatives.13

South America and Indochina subcontinent

In the late 1950's Chloroquine resistance to Plasmodium falciparum
occurred in S America and the Indochina Subcontinent. Since then it has conquered most of
the areas where the parasite species is endemic. In wide areas of South-east Asia,western
Oceania and South America Sulfadoxine/Pyrimethamine combinations have lost adequate
efficacy.13

Indonesia

Chloroquine resistance in Plasmodium vivax has recently been
recognised in Indonesia14

China

Pyronaridine is highly effective against Plasmodium falciparum and
Plasmodium vivax .It is efficacious against chloroquine-resistant strain of Plasmodium
falciparum in vitro and in vivo.9 Pyronaridine/Fansidar was used in the treatment of
chloroquine-resistant Plasmodium falciparum malaria in Hainan Province.10

Oceania

-in Papua New Guinea, Solomon Islands and Vanuatu Chloroquine
resistance is intense for Plasmodium falciparum and some reports of resistant Plasmodium
vivax. Mefloquine now the recommended regimen with Maloprim plus Chloroquine as an
alternative.2

West Africa

Chloroquine-resistant Plasmodium falciparum malaria is an emerging
problem in the West African subregion.15 Gabon(Lambarene) A substantial increase to
Chloroquine resistance in contrast to reports from neighbouring countries.16 Burkina Faso
(Africa) risk very high.2 Cameroon Two opposite situations were encountered. In Northern
Cameroon where mefloquine resistance is prevalent a close correlation was found between
the responses of Plasmodium falciparum to Mefloquine and to Quinine but not between
Mefloquine and Chloroquine.In the South where Chloroquine resistance is highly prevalent
no correlation was found between the responses to Quinine and Chloroquine or Chloroquine
and Mefloquine.The responses to Chloroquine and Quinine appear partly correlated.17

East Africa

Kenya Chloroquine resistance widespread. Deaths in British
travellers usually from malaria contracted in Africa especially Kenya. Some highland areas
of Kenya and Namibia are malaria free as is central Nairobi but the surroundings have
malaria.2

South Africa

North east, low altitude areas of north and eastern Transvaal,and
eastern Natal down to 100kms north of Durban have some Chloroquine resistance. Botswana
only in northern half of the country,Nov-J une. Swaziland high risk area Chloroquine
resistance widespread. Namibia northern third only,Nov-June.

Zimbabwe

Areas below 1200m,Nov-June; all year in Zambesi valley. Mauritius low risk except rural
areas where Chloroquine prophylaxis is appropriate.2Back to Top

Mefloquine-is an orally administered
schizonticide.Studies between 1977 and 1989 demonstrated efficacy of Mefloquine against
multidrug resistant Plasmodium falciparum.It was also effective against Plasmodium vivax.
Data about P ovale and P malariae infections were limited.Treatment failures were noted
combining Mefloquine with Sulfadoxine/Pyrimethamine.The WHO no longer recommends this
combination for malaria prophylaxis.. Mefloquine resistance is established in certain
areas of Thailand and becoming a problem in other regions of the World.Future options may
be the combination of Mefloquine with other agents such as Qinghaosu derivatives.18
Mefloquine- Preferred antimalarial for those at high risk of highly Chloroquine resistant
Plasmodium falciparum who are not in the first trimester of pregnancy,not liable to become
pregnant within three months of stopping Mefloquine, and not lactating.It gives greater
protection than other regimens in sub-saharan Africa.One 250mg tablet/week is required.It
may be used for up to a year. Pregnancy is best avoided for 3 months after stopping
prophylactic Mefloquine but pregnancy in these circumstances need not be terminated.

The main problems have been neuropsychiatric side effects The
symptoms vary and may include anxiety, depression,sleep disturbances,
nightmares,hallucinations and occasionally overt psychoses or convulsions.Symptoms usually
occur early on in the use of the drug,70% from the first 3 doses.It should not be given to
those with a history of convulsions,epilepsy in first degree relatives,or serious
psychiatric disorder. 2

A letter was published in the BMJ 24/6/95 expressing concern about
the recommended wider use of mefloquine for British travellers as recommended in above
paragraph.I.C. Perry states that of 250 mining engineers and their families based in west
Africa more than 162 developed problems which include malaise,lethargy,headache and
dizziness.Dehydration increases the frequency of side effects.Advice from the UK CAA
restricts the use of mefloquine in pilots.

G.C.Cook also reacted against the recommendation to prescribe
mefloquine and wrote to the BMJ 15/7/95. He states that Chloroquine plus Proguanil remains
moderately effective in most countries under consideration. He states that the Hospital
for Tropical Diseases receives constant reports of side effects of mefloquine
prophylaxis-many of them severe.Cross resistance exists between Mefloquine and Quinine and
the likelihood of resistance to Quinine developing is a problem. Mefloquine should be
reserved for chemotherapy of infection with Plasmodium falciparum that is resistant to
Quinine.

Five successive surveys were performed on French travellers
attitudes to prophylaxis principally in sub-saharan Africa.Chloroquine has largely been
replaced by mefloquine and by mefloquine-proguanil combination.96% of them knew the risk
of malaria and the measures of prevention19

In eastern Thailand a study was done using artemether 300mgs single
dose followed by mefloquine 750mgs at 24hrs and 500mgs at 30hrs,or oral artemether 300mgs
on day 1,followed by Mefloquine 750mgs at 24hrs and placebo at 30hrs.No serious adverse
effect was seen in either group;mild and transient nausea and vomiting and loss of
appetite were noted.The results suggested that a single oral dose of artemether(300mgs)can
markedly improve the cure rate of mefloquine in multiple drug resistant malaria.7

Mefloquine-Has the advantage of a single day regimen.Serious adverse
reactions although rare do occur and the drug cannot be used in severe malaria. The
discovery of a potentially lethal cardiotoxicity associated with Halofantrine limits its
use. The artemisinin derivatives represent an exciting breakthrough.They seem remarkably
free from adverse effects although the neurotoxicity seen in animal studies with the
liposoluble derivatives gives cause for concern.The lack of pharmokinetic and toxicity
data preclude their approval by Western drug regulation authorities.20 The sensitivity of
Plasmodium falciparum to Chloroquine, mefloquine, quinine, halofantrine, and
sulfadoxine/pyrimethamine was investigated at Lambarene in the Gabon.The highest degree of
resistance to Chloroquine ever reported from Central Africa was found in 43 isolates which
were all resistant.A significant positive correlation was found between responses to
Quinine and Mefloquine.16Back to Top

Epilepsy-Both mefloquine and chloroquine are unsuitable.In malaria
areas with no Chloroquine resistance Proguanil 200mgs daily is recommended. For
sub-saharan Africa doxycycline should be considered in spite of its side effects.
Phenytoin,carbamazepine and barbiturates shorten the half-life of doxycycline.Maloprim is
an alternative.2 Renal failure Chloroquine and Proguanil are excreted by the
kidney.Mefloquine and doxycycline are largely metabolised and excreted by the liver. 2
Splenectomy Avoid unnecessary visits to malaria areas.2 Psoriasis-Chloroquine may cause
exacerbation and is not recommended.

Plasmodium falciparum malaria infection during pregnancy contributes to low birth
weight(LBW) -one of the greatest risks for neonatal mortality.In areas hyperendemic for
Chloroquine resistant Plasmodium falciparum a two dose Sulfadoxine/Pyrimethamine is a cost
effective way to reduce LBW incidence and should be part of the antenatal care package21
Routine chemoprophylaxis appears to have an effect on antenatal morbid episodes and packed
cell volume.There is a trend towards higher birthweight in chemoprophylaxis groups.22
Pregnant women are at particular risk of severe malaria and should avoid visiting endemic
areas if feasible. Chloroquine and Proguanil have a long history of safe use during
pregnancy and mefloquine can also be used in the 2nd and 3rd trimesters.2

Children are unable to tolerate certain antimalarials due to
toxicities unique for them. some of the safest and most palatable antimalarials for
children are not available in the USA.23 Most of the fatalities occur in infants and
children under the age of 5 years.In the past 5 years sporadic cases of drug resistant
Plasmodium vivax malaria in Indonesia,IrianJaya and Papua New Guinea have been reported
especially in children.Plasmodium ovale and Plasmodium malariae remain susceptible to most
antimalarial agents. Prophylaxis in children as in adults is to use nonpharmacologic
protective strategies. Because of rare reports of toxic encephalopathy and
seizures,repellents containing DEET should be used judiciously in children. They should be
applied to exposed clothing but not to mucous membranes,open wounds or hands.Repellents
should be washed off when children come indoors to protected areas. Doxycycline is
contraindicated in children under the age of 12 years and the safety of mefloquine has not
been established in children weighing less than 15kgs14. Chloroquine remains the
prophylactic of choice in areas of no Chloroquine resistance such as the Middle East,
Central America and the Caribbean.For young children unable to take pills pulverised
powder may be mixed with food.Chloroquine is quite bitter and more palatable alternatives
eg Chloroquine suspension(Nivaquine)may be substituted.Chloroquine suspension is not
available in the USA.Prophylaxis commences 1-2weeks prior to departure and must continue
for 4 weeks after returning home.14Back to Top

In March 1988 a letter in Nature from a Columbian scientist claimed
he had a malaria vaccine. A chemical vaccine SPF66 was tested and appeared to reduce
clinical malaria by 30%. A trial in Tanzania in children also reported a 30% reduction. A
second trial in Gambia on infants 6mths-1 year showed only an 8% reduction. Dr Emanuel
Pataroya the developer of the vaccine in Columbia felt the criticism of his vaccine based
on this trial was invalid as such young babies have not yet developed their immune system
fully and the greatest incidence is in children 1-5years and up to 10years. A few more
small scale trials have been recommended.

The NEJM of January 9th 1997 reported that a malaria vaccine based
on fusion of a circumsporozoite protein and HBsAg plus a potent adjuvant could protect
against experimental challenge with P.Falciparum malaria. The circumsporozoite protein is
the principal antigen on the surface of the sporozoites.Sporozoites are injected into the
host by a bite from an infected mosquito. They rapidly invade hepatocytes and multiply-the
asymptomatic,pre-erythrocytic phase of malaria. After release from the hepatocyte they
invade erythrocytes- the asexual erythrocytic phase responsible for the symptoms of the
disease, Some of the intraerythrocytic parasites transform into gametocytes -a sexual
stage from which the the differentiated sporozoites migrate to the salivary glands of the
mosquitos. The SPF66 vaccine has been aimed at the erythrocytic phase but recent trials in
endemic areas have not confirmed the efficacy of the vaccine as was reported in my last
update. 46 subjects aged 18-45 who had not previously been exposed to malaria were
immunised in the recent study reported in the NEJM.3 formulations of the vaccine were
used. The vaccine was considered efficacious if there was no parasitologic evidence of
P.Falciparum infection after a sporozoite challenge that caused infection in 100% of
unimmunised subjects. 22 subjects who received 3 doses of vaccine agreed to a challenge
with P Falciparum sporozoites. 8 were given vaccine 1.Seven were given vaccine 2 and seven
were given vaccine3.Malaria developed in seven out of 8 subjects given vaccine 1. Five out
of 7 subjects given vaccine 2 became infected. Only one of the seven given vaccine 3
became infected. Summary of Review Although the results are encouraging work must continue
as the numbers reported on are very small and there are still many unanswered questions as
regards mechanism of action. This summary is based on the RTS,S Malaria Vaccine Evaluation
Group NEJM Jan 9,1997 Pages 86-91. Editorial Ruth S Nussenzweig MD., Ph.D and Fidel
Zavala,MD New York University Medical Centre.

Increasing areas of chloroquine resistant Plasmodium falciparum have
been reported. The use of chloroquine and/or proguanil is under extensive review and
alternative regimens using mefloquine or doxycycline have been discussed. The newer
Artemisinin derivatives show promise and are being tested particularly in Thailand.
Azithromycin has been shown in animals to be promising

Protective measures have become of increasing importance due to
serious side effects of newer drugs in particular Mefloquine. A balanced decision must be
taken based on the risk of getting Plasmodium falciparum malaria with a high mortality and
approximately 7 deaths/year in the UK weighed against serious side effects. Approximately
200,000,000 cases occur Worldwide annually and 1 or 2 million die. The greatest number of
deaths occur in small children in Sub-saharan Africa.

Malaria vaccines are not yet in use by the WHO but trials are still
being considered. The recommendations for prophylaxis vary greatly from country to country
and there is no generally accepted regime in areas of chloroquine resistance. Protective
measures plus Chloroquine and Proguanil still represent the most generally recommended
regimes together with standby drugs in areas of chloroquine resistance. Sub-saharan Africa
is a tremendous problem and in spite of potential side effects many authorities recommend
Mefloquine for this part of the World

5 Hien TT, "An overview of the clinical use of artemesinin and
its derivatives in the treatment of falciparum malaria in Viet Nam," Transactions of
the Royal Society of Tropical Medicine and Hygiene Suppl 1 (Jun 1994): S7-8